This project seeks to develop inhibitors of a novel pancreatic ductal adenocarcinoma (PDAC) protein target. PDAC remains one of the deadliest cancers with an average survival of 3.5 months for non-resectable tumors. Currently, a major obstacle in PDAC treatment is that the cells rapidly exhibit resistance to existing untargeted treatment regimens leaving patients with no further options. Studies indicate that inhibiting this novel protein target will be effective against the most severe forms of PDAC. Aim 1 of this project will expand and refine the inhibitor chemotype using computational and experimental binding measurements. Aim 2 will experimentally validate the hits from Aim 1 and assess specificity and mechanism of action of hit compounds in vitro. Finally, preliminary ADME will be assessed on the top hits. During Phase II, these data will drive medicinal chemistry design and synthesis of a lead series. Followed by in vivo toxicity, pharmacokinetics, and efficacy producing a validated and targeted PDAC therapeutic lead compound for further pre-clinical studies.